Formulations for use in inhaler devices

ABSTRACT

A formulation for an inhaler device comprises carrier particles having a diameter of at least 50 μm and a mass median diameter of at least 175 μm; active particles; and additive material to which is able to promote release of the active particles from the carrier particles on actuation of the inhaler device. The formulation has excellent flowability even at relatively high fine particle contents.

The invention relates to carrier materials for use in inhaler devices,to formulations comprising the carrier materials and to the use of theformulations.

The administration of pharmacologically active agents by inhalation is awidely used technique, especially for the treatment of diseases of therespiratory tract. The technique is also used for the administration ofcertain active agents having systemic action, which are absorbed, viathe lungs, into the bloodstream. Known inhaler devices includenebulizers, pressurised metered dose inhalers and dry powder inhalers.The present invention is primarily concerned with formulations for usein dry powder inhalers, although in some circumstances formulationsaccording to this invention may also or instead be useful in pressurisedmetered dose inhalers.

The delivery of dry powder particles of an active agent to therespiratory tract presents certain problems. The inhaler should deliverto the lungs the maximum possible proportion of the active particlesexpelled from the device, including a significant proportion to thelower lung, preferably even at the poor inhalation capabilities of somepatients, especially asthmatics. In use of many of the currentlyavailable devices, however, only a proportion, and frequently as littleas 10%, of the active particles expelled from the device on inhalationreach the lower lung.

On exit from the inhaler device, the active particles should form aphysically and chemically stable aerocolloid which remains in suspensionuntil it reaches an alveolar or other absorption site. Once at theabsorption site, the active particles should be capable of efficientcollection by the pulmonary mucosa with no active particles beingexhaled from the absorption site.

The size of the active particles is important. For effective delivery ofactive particles deep into the lungs, the active particles should besmall, with an equivalent aerodynamic diameter substantially in therange of up to 10 μm. Small particles are however thermodynamicallyunstable due to their high surface area to volume ratio, which providessignificant excess surface free energy and encourages particles toagglomerate. Agglomeration of small particles in the inhaler andadherence of particles to the walls of the inhaler can result in theactive particles leaving the inhaler as large agglomerates or in theirnot leaving the inhaler and remaining adhered to the interior thereof.

The uncertainty as to the extent of agglomeration of the particlesbetween each actuation of the inhaler and between different inhalers anddifferent batches of particles, leads to poor dose reproducibility. Ithas been found that powders are generally reproducibly fluidisable, andtherefore reliably removable from an inhaler device, when the particleshave a diameter greater than 60 μm. Good flow properties are desirablein the contexts of metering and of dispersal from the device.

To give the most effective dry powder aerosol, therefore, the particlesshould be large while in the inhalers, but small when in the respiratorytract.

It is common, in an attempt to achieve those demands, to include in thedry powder formulation carrier particles, to which the active particlescan adhere whilst in the device, the active particles then beingdispersed from the surfaces of the carrier particles on inhalation intothe respiratory tract, to give a fine suspension. It is known that thepresence of a certain amount of fine excipient material, normally of thesame material as the carrier, can improve the proportion of drugreaching the lung. The presence of such a fraction of fine excipient isconventionally limited to less than 10% and generally less than 5% dueto the catastrophic loss of flowability at higher fine particlecontents, leading to poor dose reproducibility.

The proportion of the active particles reaching the lung can beincreased by incorporating in the formulation an agent which promotesrelease of the active particle, as described in WO96/23485.

The invention provides a formulation for use in an inhaler device,comprising

-   -   carrier particles having a diameter of at least 50 μm and a mass        median diameter of at least 175 μm; active particles; and    -   additive material which is able to promote release of the active        particles from the carrier particles on actuation of the inhaler        device.

The formulation of the invention surprisingly has both excellentflowability within the device and, on expulsion from the device, permitsgood dispersion of the active particles from the carrier particles andgeneration of a relatively high fine particle fraction, promotingdelivery of a relatively large proportion of the active particles intothe lung.

The use of carrier particles of relatively large size is described inWO96/02231, but that document does not suggest the incorporation ofadditive material to promote release of the active particles from thecarrier particles. The carrier particles used in accordance with thepresent invention have a mass median diameter (MMD) of at least 175 μm.In fact, it is preferred that the MMD of the carrier particles is atleast 200 μm, and more preferably at least 250 μm.

The carrier particles have a diameter of at least 50 μm. Although asdescribed below the formulation may include particles of diameter lessthan 50 μm of the same material as the carrier particles, those smallerparticles are not included within the term “carrier particles” as usedherein. Advantageously, not more than 10% by weight, and preferably notmore than 5% by weight, of the carrier particles have a diameter of 150μm or less. Advantageously at least 90% by weight of the carrierparticles have a diameter of 175 μm or more, and preferably 200 μm ormore. Advantageously, at least 90% by weight, and preferably at least95% by weight, of the carrier particles have a diameter of not more than1 mm. Preferably at least 90% by weight of the carrier particles have adiameter of not more than 600 μm. Advantageously, at least 50% byweight, and preferably at least 60% by weight, of the carrier particleshave a diameter of 200 μm or more. Preferably, at least 90% by weight ofthe carrier particles have a diameter between 150 μm and 750 μm, morepreferably between 150 μm and 650 μm. Particular advantages are offeredby formulations in which substantially all of the carrier particles havea diameter in the range of about 210 to about 360 μm or from about 350to about 600 μm.

The carrier particles may be of any acceptable pharmacologically inertmaterial or combination of materials. For example, the carrier particlesmay be composed of one or more materials selected from sugar alcohols;polyols, for example sorbitol, mannitol and xylitol, and crystallinesugars, including monosaccharides and disaccharides; inorganic saltssuch as sodium chloride and calcium carbonate; organic salts such assodium lactate; and other organic compounds such as urea,polysaccharides, for example starch and its derivatives;oligosaccharides, for example cyclodextrins and dextrins. Advantageouslythe carrier particles are of a crystalline sugar, for example, amonosaccharide such as glucose or arabinose, or a disaccharide such asmaltose, saccharose, dextrose or lactose. Preferably, the carrierparticles are of lactose.

The carrier particles are preferably of a material having a fissuredsurface, that is, on which there are clefts and valleys and otherrecessed regions, referred to herein collectively as fissures. Thefissures should preferably be a least 5 μm wide extending to at least 5μm deep, preferably at least 10 μm wide and 10 μm deep and mostpreferably at least 20 μm wide and 20 μm deep.

Because of the excellent flow properties of the formulations containingthe fissured carrier particles, the formulations offer specialadvantages in the administration of active agents to be administered inrelatively large doses. Thus, whereas formulations containingconventional lactose carriers and fine particle contents of above 5%tend to have poor flow properties, with flow properties at fine particlecontents above 10% being very poor, the formulations of the inventionmay have adequate flow properties even at fines contents (that iscontents of active particles and of any fine particles of additivematerial, together with any other particles of aerodynamic diameter ofnot more than 20 μm) of up to 90% by weight, based on the total weightof fines and carrier particles. Moreover, the fissured carrier particlesoffer particular advantages in that they are capable of retainingrelatively large amounts of fine material in the fissures without orwith only little segregation. That is thought to underly the goodrespirable fraction that is generated in use of the formulations and isespecially advantageous in use of the carrier particles with certainadditive materials, for example, magnesium stearate, which tend to causesegregation of the components, permitting increased amounts of suchadditive materials to be used without increasing segregation tounacceptable levels. Advantageously, the fines content is not more than50% by weight, and more preferably not more than 20% by weight, based onthe total weight of fines and carrier particles. Preferably, the finescontent is at least 5% by weight, based on the total weight of fines andcarrier particles. The invention offers particular advantages in thecase of formulations containing at least 10%, for example, from 10 to20% by weight fines or at least 20%, for example from 20 to 50% byweight fines, in each case, based on the total weight of fines andcarrier particles. The fines content may include from 0.1 to 99% byweight active particles, for example from 0.1 to 90% by weight, andadvantageously from 0.1 to 80% by weight active particles, in each casebased on the total weight of fines. In many cases, however, the activeparticles will constitute less than half of the total weight of fines.

A number of methods may be used to determine whether carrier particleshave a fissured surface that will offer the above-mentioned capabilityof retaining relatively large fines contents substantially withoutsegregation:

1. Determination of Tapped Density.

The tapped density of the fissured carrier particles may be about 6% ormore, and preferably 15% or more, lower than the tapped density ofcarrier particles of the same material and of particle characteristicsof a kind typical of carrier particles which have conventionally beenused in the manufacture of inhalable powders. In the case of fissuredcarrier particles of crystalline sugars, for example lactose, the tappeddensity of the fissured particles is not more than 0.75 g/cm³, andpreferably not more than 0.70 g/cm³. The tapped density of lactosegrades conventionally used in the manufacture of commercial DPIformulations is typically about 0.8 g/cm³. Tapped densities referred toherein may be measured as follows:

A measuring cylinder is weighed on a top pan balance (2 place).Approximately 50 g powder is introduced into the measuring cylinder, andthe weight is recorded. The measuring cylinder containing the powder isattached to a jolting volumeter (Jel Stampfvolumeter). The joltingvolumeter is set to tap 200 times. During each tap, the measuringcylinder is raised and allowed to fall a set distance. After the 200taps, the volume of the powder is measured. The tapping is repeated andthe new volume measured. The tapping is continued until the powder willsettle no more. The tapped density is calculated as the weight of thepowder divided by the final tap volume. The procedure is performed threetimes (with new powder each time) for each powder measured, and the meantapped density calculated from those three final tapped volume values.

2. Mercury Intrusion Porosimetry.

Mercury intrusion porosimetry assesses the pore size distribution andthe nature of the surface and pore structure of the particles.Porosimetry data is suitably collected over pressure range 3.2 kPa to8.7 MPa, for example, using an Autopore 9200 II Porosimeter(Micromeritics, Norcross, USA). Samples should be evacuated to below 5Pa prior to analysis to remove air and loosely bound surface water.Suitable lactose is characterised by a bulk density of not more than0.65 g/cm³ and preferably not more than 0.6 g/cm³. Suitable lactose isalso characterised by a total intrusion volume measured by mercuryintrusion porosimetry of at least 0.8 cm³g⁻¹ and preferably at least 0.9cm³g⁻¹. (It has been found that lactose having a bulk density of 0.6g/cm³ as measured by mercury intrusion porosimetry has a tapped densityof about 0.7 g/cm³, whereas the discrepancy between the two methods atlower densities is less.)

3. “Fissure Index”.

The term “fissure index” used herein refers to the ratio of atheoretical envelope volume of the particles, as calculated from theenvelope of the particles, to the actual volume of the particles, thatis, omitting fissures within the envelope. Suitable particles are thosehaving a fissure index of at least 1.25. The theoretical envelope volumemay be determined optically, for example, by examining a small sample ofthe particles using an electron microscope. The theoretical envelopevolume of the particles may be estimated via the following method. Anelectron micrograph of the sample may be divided into a number of gridsquares of approximately equal populations, each containing arepresentative sample of the particles. The population of one or moregrids may then be examined and the envelope encompassing each of theparticles determined visually as follows. The Feret's diameter forparticles within a grid is measured relative to a fixed axis of theimage. Typically at least ten particles are measured for their Feret'sdiameter. Feret's diameter is defined as the length of the projection ofa particle along a given reference line as the distance between theextreme left and right tangents that are perpendicular to the referenceline. A mean Feret's diameter is derived. A theoretical mean envelopevolume may then be calculated from this mean diameter to give arepresentative value for all the grid squares and thus the whole sample.Division of that value by the number of particles gives the mean valueper particle. The actual volume of the particles may then be calculatedas follows. First, the mean mass of a particle is calculated. A sampleof approximately 50 mg is taken and its precise weight recorded to 0.1mg. Then by optical microscopy the precise number of particles in thatsample is determined. The mean mass of one particle can then bedetermined. The procedure is then repeated five times to obtain a meanvalue of this mean. Second, a fixed mass of particles (typically 50 g),is weighed out accurately, and the number of particles within this massis calculated using the above mean mass value of one particle. Finally,the sample of particles is immersed in a liquid in which the particlesare insoluble and, after agitation to remove trapped air, the amount ofliquid displaced is measured. From this the mean actual volume of oneparticle can be calculated. The fissure index is advantageously not lessthan 1.5, and is, for example, 2 or more.

4. “Rugosity Coefficient”.

The rugosity coefficient is used to mean the ratio of the perimeter of aparticle outline to the perimeter of the ‘convex hull’. This measure hasbeen used to express the lack of smoothness in the particle outline. The‘convex hull’ is defined as a minimum enveloping boundary fitted to aparticle outline that is nowhere concave. (See “The Shape ofPowder-Particle Outlines” A. E. Hawkins, Wiley.) The ‘rugositycoefficient’ may be calculated optically as follows. A sample ofparticles should be identified from an electron micrograph as identifiedabove. For each particle the perimeter of the particle outline and theassociated perimeter of the ‘convex hull’ is measured to provide therugosity coefficient. This should be repeated for at least ten particlesto obtain a mean value. The mean rugosity coefficient is at least 1.25.

Carrier particles which have the above-mentioned capability of retainingrelatively large amounts of fine material without or with only littlesegregation will generally comply with all of Methods 1 to 4 above, butfor the avoidance of doubt any carrier particles which comply with atleast one of Methods 1 to 4 is deemed to be a fissured particle.

The carrier particles are advantageously in the form of an agglomerateconsisting of a plurality of crystals fused to one another, the fastnessof agglomeration being such that the carrier particles havesubstantially no tendency to disintegrate on expulsion from the inhalerdevice. In the case of crystalline sugars, such as lactose, suchstructures may be obtained in a wet granulation process, in whichcrystals within an agglomerate become fused to one another by solidbridges, the resultant structure having a complex shape of highirregularity and/or high fractal dimension, including a multiplicity ofclefts and valleys, which in some cases may be relatively deep. Eachagglomerate will generally contain at least three lactose primarycrystals of the characteristic tomahawk shape.

Such agglomerates are clearly distinguished from agglomerates of thekind which form in powder formulations by aggregation of particles,which do tend to disintegrate on expulsion from the inhaler.

Suitably shaped carrier particles also include dendritic spherulites ofthe type disclosed in U.S. Pat. No. 4,349,542 for use in tablemanufacture.

The carrier particles advantageously constitute at least 50%, preferablyat least 60% and especially at least 70% by weight of the formulation,based on the total weight of the formulation.

The additive material, which is preferably on the surfaces of thecarrier particles, promotes the release of the active particles from thecarrier particles on actuation of the inhaler device. The formulationcontaining the additive material should, however, be such that theactive particles are not liable to be released form the carrierparticles before actuation of the inhaler device. The additive material,which it will be appreciated is of a different material from the carrierparticles, may be in the form of particles, the additive particles beingattached to the surfaces of the carrier particles.

In International Specification WO 96/23485 many examples are given ofadditive materials which are such that the active particles are notliable to be released from the carrier particles before actuation of theinhaler device but are released during use of the inhaler device.“Actuation of the inhaler device” refers to the process during which adose of the powder is removed from its rest position in the inhalerdevice, usually by a patient inhaling. That step takes place after thepowder has been loaded into the inhaler device ready for use.

If it is desired to test whether or not the active particles of a powderare liable to be released from the carrier particles before actuation ofthe inhaler device a test can be carried out. A suitable test isdescribed in International Specification WO96/23485 (Example 12 and 13).A powder whose post-vibration homogeneity measured as a percentagecoefficient of variation, after being subjected to the described test,is less than about 5% can be regarded as acceptable.

It is believed that additive material is attracted to and adheres tohigh energy sites on the surfaces of the carrier particles. Onintroduction of the active particles, many of the high energy sites arenow occupied, and the active particles therefore occupy the lower energysites on the surfaces of the carrier particles. That results in theeasier and more efficient release of the active particles in the airstream created on inhalation, thereby giving increased deposition of theactive particles in the lungs.

However, as indicated above, it has been found that the addition of morethan a small amount of additive material can be disadvantageous becauseof the adverse effect on the ability to process the mix duringcommercial manufacture.

It is also advantageous for as little as possible of the additivematerial to reach the lungs on inhalation of the powder. Although theadditive material will most advantageously be one that is safe to inhaleinto the lungs, it is still preferred that only a very small proportion,it any, of the additive material reaches the lung, in particular thelower lung. The considerations that apply when selecting the additivematerial and other features of the powder are therefore different fromthe considerations when a third component is added to carrier and activematerial for certain other reasons, for example to improve absorption ofthe active material in the lung, in which case it would of course beadvantageous for as much as possible of the additive material in thepowder to reach the lung.

The optimum amount of additive material will depend on the chemicalcomposition and other properties of the additive material. In general,the amount of additive will be not more than 50% by weight, based on thetotal weight of the formulations. However, it is thought that for mostadditives the amount of additive material should be not more than 10%,more advantageously not more than 5%, preferably not more than 4% andfor most materials will be not more than 2% or even not more than 1% byweight or not more than 0.25% based on the total weight of theformulation. In general, the amount of additive material is at least0.01% by weight based on the total weight of the formulation.

Advantageously the additive material is an anti-adherent material andwill tend to decrease the cohesion between the anti-adherent materialsand the carrier particles. In order to determine whether a givenmaterial is an anti-adherent material, the test described inInternational Specification WO97/03649 (pages 6 and 7) using an“Aeroflow” apparatus may be used, anti-adherent materials being thoseadditive materials that result in a lowering of the mean time betweenavalanches of the powder, as compared with the powder in the absence ofthe additive material.

Advantageously the additive material is an anti-friction agent (glidant)and will give better flow of powder in the dry powder inhaler which willlead to a better dose reproducibility from the inhaler device.

Where reference is made to an anti-adherent material, or to ananti-friction agent, the reference is to include those materials whichwill tend to decrease the cohesion between the active particles and thecarrier particles, or which will tend to improve the flow of powder inthe inhaler, even though they may not usually be referred to asanti-adherent material or an anti-friction agent. For example, leucineis an anti-adherent material as herein defined and is generally thoughtof as an anti-adherent material but lecithin is also an anti-adherentmaterial as herein defined, even though it is not generally though of asbeing anti-adherent, because it will tend to decrease the cohesionbetween the active particles and the carrier particles. Advantageously,the additive material consists of physiologically acceptable material.As already indicated, it is preferable for only small amounts ofadditive material to reach the lower lung, and it is also highlypreferable for the additive material to be a material which may besafely inhaled into the lower lung where it may be absorbed into theblood stream. That is especially important where the additive materialis in the form of particles.

The additive material may include a combination of one or morematerials.

It will be appreciated that the chemical composition of the additivematerial is of particular importance.

It will furthermore be appreciated that additive materials that arenaturally occurring animal or plant substances will offer certainadvantages.

Advantageously, the additive material includes one or more compoundsselected from amino acids and derivatives thereof, and peptides andpolypeptides having molecular weight from 0.25 to 100 Kda, andderivatives thereof. Amino acids, peptides or polypeptides and theirderivatives are both physiologically acceptable and give acceptablerelease of the active particles on inhalation.

It is particularly advantageous for the additive material to comprise anamino acid. Amino acids have been found to give, when present in lowamounts in a powder as additive material, high respirable fraction ofthe active materials with little segregation of the powder and also withvery little of the amino acid being transported into the lower lung. Inrespect of leucine, a preferred amino acid, it is found that, forexample, for an average dose of powder only about 10 μg of leucine wouldreach the lower lung. The additive material may comprise one or more ofany of the following amino acids: leucine, isoleucine, lysine, valine,methionine, phenylalanine. The additive may be a salt of a derivative ofan amino acid, for example aspartame or acesulfame K. Preferably, theadditive particles consist substantially of leucine, advantageouslyL-leucine. As indicated above, leucine has been found to giveparticularly efficient release of the active particles on inhalation.Whilst the L-form of an amino acid is used in Examples described below,the D- and DL-forms may also be used.

Additive materials which comprise one or more water soluble substancesoffer certain advantages. This helps absorption of the substance by thebody if the additive reaches the lower lung. The additive material mayinclude dipolar ions, which may consist of zwitterions.

Alternatively, the additive material may comprise particles of aphospholipid or a derivative thereof. Lecithin has been found to be agood material for the additive material.

The additive material may include or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble, for example lecithin, inparticular soya lecithin, or substantially water insoluble, for examplesolid state fatty acids such as lauric acid, palmitic acid, stearicacid, erucic acid, behenic acid, or derivatives (such as esters andsalts) thereof. Specific examples of such materials are: magnesiumstearate; sodium stearyl fumarate; sodium stearyl lactylate;phospatidylcholines, phosphatidylglycerols and other examples of naturaland synthetic lung surfactants; liposomal formulations; lauric acid andits salts, for example, sodium lauryl sulphate, magnesium laurylsulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugaresters in general.

Other possible additive materials include talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch.

The expression “additive material” as used herein does not includecrystalline sugars. Whereas small particles of one or more crystallinesugars may be present, and are indeed preferred to be present, asdescribed below, formulations which contain small crystalline sugarparticles will also contain a further substance which is an additivematerial in the sense in which that expression is used herein.

In the case of certain additive materials, it is important for theadditive material to be added in a small amount. For example, magnesiumstearate is highly surface active and should therefore be added in smallamounts, for example, up to 2.5%, by weight based on the weight of theformulation with amounts of from 0.1 to 2% being preferred, for example,0.5% to 1.7% especially 0.75 to 1.5% by weight. In some cases, it mightbe found advantageous to use smaller amounts of magnesium stearate, forexample, from 0.02 to 0.6%, or 0.2 to 0.4% by weight.Phosphatidylcholines and phosphatidylgycerols on the other hand are lessactive and can usefully be added in greater amounts. In respect ofleucine, which is still-less active, an addition of 2% by weight leucinebased on the weight of the powder gives good results in respect of therespirable fraction of the active particles, low segregation and lowamount of leucine reaching the lower lung; it is explained in WO96/23485 that an addition of a greater amount does not improve theresults and in particular does not significantly improve the respirablefraction and therefore whilst even with 6% leucine a reasonable resultis obtained that is not preferred since it results in an increasedquantity of additive material being taken into the body and willadversely affect the processing properties of the mix. In the preferredformulations of the present invention using fissured carrier particles,however, it has been found that increased amounts of additive materialmay be used and give improved respirable fractions.

The additive material will often be added in particulate form but it maybe added in liquid or solid form and for some materials, especiallywhere it may not be easy to form particles of the material and/or wherethose particles should be especially small, it may be preferred to addthe material in a liquid, for example as a suspension or a solution oras a melt. Even then, however, the additive material of the finishedpowder may be in particulate form. An alternative possibility, however,that is within the scope of the invention is to use an additive materialwhich remains liquid even in the final essentially particulate materialwhich can still be described as a “dry powder”.

In some cases improved clinical benefits will be obtained where theadditive material is not in the form of particles of material. Inparticular, the additive material is less likely to leave the surface ofthe carrier particle and be transported into the lower lung.

Where the additive material of the finished powder is particulate, thenature of the particles may be significant. The additive particles maybe non-spherical in shape. Advantageously, the additive particles areplate-like particles. Alternatively, the additive particles may beangular for example prisms, or dendritic in shape. Additive particleswhich are non-spherical may be easier to remove from the surfaces of thecarrier particles than spherical, non-angular particles and plate-likeparticles may give improved surface interaction and glidant actionbetween the carrier particles.

The surface area of the additive particles is also thought to beimportant. The surface area of the additive particles, as measured usinggas absorption techniques, is preferably at least 5 m²g⁻¹. In many casesit is found that additive material comprising small plate-like particlesis preferred.

Advantageously, at least 90% by weight of the additive particles have anaerodynamic diameter less than 150 μm, more advantageously less than 100μm, preferably less than 50 μm. Advantageously, the MMAD of the additiveparticles is not more than 20 μm, preferably not more than 15 μm, andmore preferably not more than 10 μm. The additive particles preferablyhave a mass median diameter less than the mass median diameter of thecarrier particles and will usually have a mass median diameter ofapproximately between a tenth and a thousandth, for example, between afiftieth and a five hundredth that of the carrier particles. The MMAD ofthe additive particles will generally be not less than 0.1 μm, forexample, not less than 1 μm.

The amount of additive material will depend upon the nature of theadditive material, and will generally be at least 0.01% based on theweight of the carrier particles. In the case of additive materials thatdo not tend to segregate from the carrier particles, the additivematerial may be present in amounts of up to 50%, by weight, based on theweight of the carrier particles and additive. Advantageously, theadditive material may constitute up to one third of the combined weightof additive and carrier particles. In general, the amount of additivematerial will not exceed 1.0%, and preferably not exceed 5%, of thecombined weight of additive and carrier particles.

In the use of those additive materials which do have a tendency tosegregate, the amount of additive material will generally be less than5%, for example not more than 3% by weight based on the combined weightof additive material and carrier particles.

The active particles referred to throughout the specification willcomprise an effective amount of at least one active agent that hastherapeutic activity when delivered into the lung. The active particlesadvantageously consist essentially of one or more therapeutically activeagents. Suitable therapeutically active agents may be drugs fortherapeutic and/or prophylactic use. Active agents which may be includedin the formulation include those products which are usually administeredorally by inhalation for the treatment of disease such a respiratorydisease, for example, β-agonists.

The active particles may comprise at least one β₂-agonist, for exampleone or more compounds selected from terbutaline, salbutamol, salmeteroland formoterol. If desired, the active particles may comprise more thanone of those active agents, provided that they are compatible with oneanother under conditions of storage and use. Preferably, the activeparticles are particles of salbutamol sulphate. References herein to anyactive agent are to be understood to include any physiologicallyacceptable derivative. In the case of the β₂-agonists mentioned above,physiologically acceptable derivatives include especially salts,including sulphates.

The active particles may be particles of ipatropium bromide.

The active particles may include a steroid, which may be beclometasonedipropionate or may be fluticasone. The active principle may include acromone which may be sodium cromoglycate or nedocromil. The activeprinciple may include a leukotriene receptor antagonist.

The active particles may include a carbohydrate, for example heparin.

The active particles may advantageously comprise a therapeuticallyactive agent for systemic use provided that that agent is capable ofbeing absorbed into the circulatory system via the lungs. For example,the active particles may comprise peptides or polypeptides or proteinssuch as DNase, leukotrienes or insulin (including substituted insulinsand pro-insulins), cyclosporin, interleukins, cytokines, anti-cytokinesand cytokine receptors, vaccines (including influenza, measles,‘anti-narcotic’ antibodies, meningitis), growth hormone, leuprolide andrelated analogues, interferons, desmopressin, immunoglobulins,erythropoeitin, calcitonin and parathyroid hormone. The formulation ofthe invention may in particular have application in the administrationof insulin to diabetic patients, thus avoiding the normally invasiveadministration techniques used for that agent.

The formulations of the invention may advantageously be for use in painrelief. Non-opioid analgesic agents that may be included as pain reliefagents are, for example, alprazolam, amitriptyline, aspirin, baclofen,benzodiazepines, bisphosphonates, caffeine, calcitonin,calcium-regulating agents, carbamazepine, clonidine, corticosteroids,dantrolene, dexamethasone, disodium pamidronate, ergotamine, flecainide,hydroxyzine, hyoscine, ibuprofen, ketamine, lignocaine, lorazepam,methotrimeprazine, methylprednisolone, mexiletine, mianserin, midazolam,NSAIDs, nimodipine, octreotide, paracetamol, phenothiazines,prednisolone, somatostatin. Suitable opioid analgesic agents are:alfentanil hydrochloride, alphaprodine hydrochloride, anileridine,bezitramide, buprenorphine hydrochloride, butorphanol tartrate,carfentanil citrate, ciramadol, codeine, dextromoramide,dextropropoxyphene, dezocine, diamorphine hydrochloride, dihydrocodeine,dipipanone hydrochloride, enadoline, eptazocine hydrobromide,ethoheptazine citrate, ethylmorphine hydrochloride, etorphinehydrochloride, fentanyl citrate, hydrocodone, hydromorphonehydrochloride, ketobemidone, levomethadone hydrochloride, levomethadylacetate, levorphanol tartrate, meptazinol hydrochloride, methadonehydrochloride, morphine, nalbuphine hydrochloride, nicomorphinehydrochloride, opium, hydrochlorides of mixed opium alkaloids,papaveretum, oxycodone, oxymorphone hydrochloride, pentamorphone,pentazocine, pethidine hydrochloride, phenazocine hydrobromide,phenoperidine hydrochloride, picenadol hydrochloride, piritramide,propiram furmarate, remifentanil hydrochloride, spiradoline mesylate,sufentanil citrate, tilidate hydrochloride, tonazocine mesylate,tramadol hydrochloride, trefentanil.

The technique could also be used for the local administration of otheragents for example for anti cancer activity, anti-virals, antibiotics,muscle relaxants, antidepressants, antiepileptics or the local deliveryof vaccines to the respiratory tract.

The active particles advantageously have a mass median aerodynamicdiameter in the range of up to 15 μm, for example from 0.01 to 15 μm,preferably from 0.1 to 10 μm, for example, from 1 to 8 μm. Mostpreferably, the mass median aerodynamic diameter of the active particlesis not exceeding 5 μm. The active particles are present in an effectiveamount, for example, at least 0.01% by weight, and may be present in anamount of up to 90% by weight based on the total weight of carrierparticles, additive materials and active particles. Advantageously, theactive particles are present in an amount not exceeding 60% by weightbased on the total weight of carrier particles, additive particles andactive particles.

It will be appreciated that the proportion of active agent present willbe chosen according to the nature of the active agent. In many cases, itwill be preferred for the active agent to constitute no more than 10%,more preferably no more than 5%, and especially no more than 2% byweight based on the total weight of carrier particles, additiveparticles and active particles.

The formulation may further comprise fine particles of an excipientmaterial, that is to say, particles of aerodynamic diameter not morethan 50 μm, of a substantially inert pharmacologically acceptablematerial. The excipient material may be any substantially inert materialthat is suitable for use as an excipient in an inhalable formulation.The excipient material preferably comprises one or more crystallinesugars, for example, dextrose and/or lactose. Most preferably theexcipient material consists essentially of lactose.

Advantageously, the fine excipient particles are of the same material asthe carrier particles. It is especially preferred for the carrierparticles and the fine excipient particles to be of lactose.

Advantageously, at least 90% by weight of the fine excipient particleshave an aerodynamic diameter of not more than 40 μm. The fine excipientparticles advantageously have an MMAD of not more than 20 μm, preferablynot more than 15 μm, more preferably not more than 10 μm, and especiallynot more than 8 μm. The MMAD of the fine excipient particles willgenerally be not less than 0.1 μm, for example not less than 1 μm.Advantageously the fine excipient particles are present in an amount ofup to 50%, for example from 0.1 to 20%, and preferably from 1 to 15%, byweight based on the total weight of the formulation.

Where fine excipient particles are present, they may be present in anamount of up to 99% by weight of the total weight of fine excipientparticles and additive material. Advantageously, fine excipientparticles are present in an amount of at least 30%, preferably at least50% and especially at least 90% by weight, based on the total weight offine excipient particles and additive material. The fine excipientparticles and additive material, advantageously constitute from 5%, orfrom 10% to two thirds by weight of the total weight of fine excipientparticles, additive material and carrier particles.

Where, as is preferred, the carrier particles and the fine excipientparticles are of the same compound, for example, lactose, it may befound convenient to consider all the particles of that compound havingan aerodynamic diameter of less than 50 μm to be fine excipientparticles, whilst particles of aerodynamic diameter of 50 μm or more areregarded as carrier particles.

The advantageous flow properties of formulations of the invention may bedemonstrated, for example, using a Flodex Tester, which can determine aflowability index over a scale of 4 to 40 mm, corresponding to a minimumorifice diameter through which smooth flow of the formulation occurs inthe Tester. The flowability index, when so measured, of formulations ofthe invention containing fissured lactose will generally be below 12 mm,even where fine particle contents (that is, particles of aerodynamicdiameter less than 50 μm or preferably less than 20 μm) exceed 10% byweight of the formulation.

The invention provides a formulation for use in a dry powder inhaler,comprising more than 5%, preferably more than 10% by weight, based onthe total weight of the formulation, of particles of aerodynamicdiameter less than 20 μm, the formulation having a flowability index of12 mm or less. The term “flowability index” as used herein refers toflowability index values as measured using a Flodex Tester.

In addition to the carrier particles, active particles and fineexcipient particles, the formulation may comprise one or more furtheradditives suitable for use in inhaler formulations, for example,flavourings, lubricants, and flow improvers. Where such furtheradditives are present, they will generally not exceed 10% by weight ofthe total weight of the formulation.

The formulations of the invention may be made by combining thecomponents in any suitable manner. In a preferred method, however, theformulations are made by mixing the additive and fine excipientparticles in a high energy mixing step, mixing the composite particlesso obtained with the carrier particles, and adding to the mixture soobtained the at least one active ingredient. In another advantageousmethod, additive particles and excipient particles are co-micronised soas to significantly reduce their particle size, the co-micronisedparticles are mixed with the carrier particles, and the at least oneactive ingredient is added to the mixture so obtained. Suitable mixersfor carrying out a high energy mixing step in the context of suchformulations are high shear mixers. Such mixers are known to thoseskilled in the art, and include, for example, the Cyclomix and theMechano-Fusion mixers manufactured by Hosokawa Micron. It will beappreciated by those skilled in the art that other suitable apparatusfor use in a high energy mixing step will include, for example, ballmills and jet mills, provided that the equipment and conditions are soarranged to effect the desired high energy mixing.

The formulation may be a powder formulation for use in a dry powderinhaler. The formulation may be suitable for use in a pressurisedmetered dose inhaler.

One embodiment of the invention will now be described in detail withreference to the accompanying illustrations in which:

FIG. 1 is a scanning electron micrograph (SEM) of a relatively highlyfissured lactose particle;

FIG. 2 is an SEM at lower magnification than FIG. 1 showing a number oflactose particles;

FIG. 3 is an SEM of a lactose carrier particle loaded with leucine andsalbutamol sulphate; and

FIG. 4 is an SEM of a formulation containing conventional lactosecarrier particles and fine excipient particles.

With reference to FIG. 1, it may be seen that the lactose carrierparticle consists of a number of individual lactose crystals which arefused to one another. The crystals define between them at the surface ofthe particle a multiplicity of relatively deep fissures or crevices.Such particles are known and have previously been regarded as suitablefor use in tablet manufacture. Surprisingly, it has been found thatcarrier particles such as that shown in FIG. 1 are able to enhance thefine particle fraction of an active substance in the presence ofadditive. The active substance, together with the fine excipient, tendbecause of their small particle size and consequent high surface energyto adhere to the carrier particles. Adhesion occurs predominantly withinthe fissures and crevices. Due to the optimum width, depth and shape ofthe fissures, the resultant loaded carrier particles have good stabilityagainst deagglomeration within the inhaler device and yet permiteffective dispersion of the active particles and fine excipient onexpulsion from the device after actuation.

FIG. 2 shows a group of carrier particles similar to that of FIG. 1.

Referring to FIGS. 3 and 4, the lactose carrier particle of FIG. 3 holdsthe fine material, consisting of leucine as additive material andsalbutamol sulphate as active material, within the fissures of itsagglomerated structure to form a relatively cohesive structure, whilstin the conventional formulation of FIG. 4 much of the fine material isnot adhered to the lactose carrier particles. The conventional carrierparticles are typically crystals which have the characteristic tomahawkshape of lactose crystals. They may also be amorphous in shape, butrarely consist of more than two fused crystals. Thus the conventionalcarrier particles are substantially without the clefts and valleys: ofthe fissured particles used in accordance with the present invention.

References herein to a “diameter” in relation to carrier particles meansthe diameter determined using laser diffraction, for example, using aMalvern Mastersizer, and references herein to a “mass median diameter”in relation to carrier particles is to be interpreted accordingly.

It may be found convenient to determine the diameters of particles in aformulation according to the invention by dispersing the particles in aliquid that does not dissolve any of the component particles, sonicatingto ensure complete dispersion, and analysing the dispersion by means oflaser diffraction, for example using a Malvern Mastersizer. That methodwill be suitable where separate analysis of fine particles of differentmaterials is unnecessary.

In practice, it may be desired to examine a larger particle sizefraction separately from a smaller size fraction. In that case, an airjet sieve may be used to effect separation. A mesh corresponding to thedesired diameter at which the separation is to be effected is then usedin the air jet sieve. A mesh corresponding to a diameter of 50 μm maythus be used for separation, larger particles being retained by thesieve whilst smaller particles pass through to be collected on a filter.That enables different techniques to be applied to analysis of thelarger particles (≧50 μm) and the smaller particles (<50 μm) if desired.

In the case of particles of the size of the carrier particles used inaccordance with the invention, the diameter as measured using laserdiffraction approximates the aerodynamic diameter. If preferred,therefore, the aerodynamic diameters of the carrier particles may bedetermined and the mass median aerodynamic diameter (MMAD) calculatedtherefrom.

MMADs referred to herein in relation to additive materials, fineexcipient particles and active particles may be measured using anysuitable technique, for example, using an impactor such as a cascadeimpactor, and analysing the size fractions so obtained, for exampleusing HPLC.

Alternatively, respective samples of the formulation may each be treatedwith a solvent that is known to disolve one or more, but not all, of theingredients and examining the undisolved particles by any suitablemethod, for example, laser diffraction.

The Following Examples Illustrate the Invention.

EXAMPLE 1

20 g of Microfine lactose (Burculo—MMAD about 8 μm) and 0.4 g ofL-leucine (Ajinomoto) were combined and placed in a stainless steel ballmill, filled with stainless steel balls of varying diameter toapproximately 50% of the mill volume. The mill was rotated atapproximately 60 RPM for about 120 minutes. The milled material (MMADabout 5 μm) was then recovered from the mill and from the surface of theballs, and is referred to below as the fines.

8 g of sieved Prismalac lactose was weighed into a glass vessel.Prismalac (trade mark) lactose is sold in the UK by Meggle for use intablet manufacture. The lactose, as purchased, had been sieved on astack of sieves in order to recover the sieve fraction passing through a600 μm mesh sieve, but not passing through a 355 μm mesh sieve. Thatfraction is referred to below as 355-600 Prismalac and has a mean tappeddensity of 0.49 g/cm³ and a bulk density as measured by mercuryintrusion porosimetry of 0.47 g/cm³.

1 g of the fines obtained as described above, and 1 g of micronisedsalbutamol sulphate (MMAD˜2 μm) was added to the 355-600 Prismalac inthe glass vessel. The glass vessel was sealed and the vessel located ina “Turbula” tumbling blender. The vessel and contents were tumbled forapproximately 30 minutes at a speed of 42 RPM.

The formulation so obtained was loaded into size 3 gelatin capsules at20 mg per capsule. The loaded capsules were rested for a period of 24hours. Three capsules were then fired sequentially into a Twin StageImpinger from a Cyclohaler at a flow rate of 60 litres per minutes, witha modified stage 1 jet of 12.5 mm internal diameter, which was estimatedto produce a cut-off diameter of 5.4 μm. The operation of the Twin StageImpinger is described in WO95/11666. Modification of a conventional TwinStage Impinger, including the use of modified stage 1 jets, is describedby Halworth and Westmoreland (J. Pharm. Pharmacol. 1987, 39:966-972).

TABLE 1 Compar- Compar- Example 1 ison 1 ison 2 355-600 Prismalac 8 g  80% 8 g 4 g lactose Salbutamol sulphate 1 g   10% 1 g 0.5 g Microfinelactose 0.9804 g 9.804% — 0.5 g Leucine 0.0196 g 0.196% — Fine particle50% 10% 40% fraction

The composition of the formulation is summarised in Table 1 above.

As shown in Table 1, the fine particle fraction is improved in thepresence of added fine lactose (Comparison 2) as compared with aformulation which contains no added fine lactose (Comparison 1). Thebest performance is obtained from the formulation according to theinvention, containing leucine as well as fine lactose. On omission ofthe Prismalac from the ingredients of Example 1, the formulation wasfound to have very poor flow properties, preventing reliable andreproducible metering. As a result, the fine particle fraction was foundto be very variable.

EXAMPLE 2

Example 1 was repeated using micronised budesonide (MMAD 2 μm) in placeof salbutamol sulphate, and magnesium stearate in place of leucine. Theresults are summarised in Table 2, which also indicates the amounts ofeach ingredient.

TABLE 2 355-600 Prismalac 4 g 80% lactose Budesonide 0.5 g 10% Microfinelactose 0.45 g  9% Magnesium stearate 0.05 g  1% Fine particle 40%fraction

EXAMPLE 3

Example 1 was repeated using Prismalac lactose which had been sieved,the sieve fractions of 212 to 355 μm (with mean tapped density 0.65g/cm³ and a bulk density as measured by mercury instrusion porosimetryof 0.57 g/cm³) being recovered and used instead of the 355-600 Prismalaclactose used in Example 1. Once again, a fine particle fraction of about50% was obtained.

EXAMPLE 4

Example 1 was repeated replacing the leucine by one of the following:lecithin, stearylamine, magnesium stearate, and sodium stearyl fumarate.

The results are summarised in Table 3.

TABLE 3 Additive Fine particle fraction Lecithin 50% Stearylamine 50%Purified phosphatidyl cholines 35% Sodium stearyl fumarate 40%

EXAMPLE 5

Micronised salbutamol sulphate was mixed with 5% by weight of sublimedL-leucine in a blender. The mixture so obtained was then tumbled in theratio of 1:6 with Prismalac (355 to 600 μm fraction) for 15 minutes. Thefine particle fraction, determined using a Twin Stage Impinger modifiedas described in Example 1, was 65%.

EXAMPLE 6

95 g of Microfine lactose (Borculo) was placed in a ceramic millingvessel (manufactured by the Pascall Engineering Company). 5 g ofadditive material (L-leucine) and the ceramic milling balls were added.The ball mill was tumbled at 60 rpm for 5 hours. The powder wasrecovered by sieving to remove the milling balls.

0.9 g of the composite excipient particles so obtained containing 5%l-leucine in Microfine lactose was blended with 0.6 g of budesonide byhand in a mortar. This blending could also be performed, for example, ina high shear blender, or in a ball mill or in a centrifugal mill. 20parts by weight of this powder were blended with 80 parts by weight of acoarse carrier lactose (sieve-fractionated Prismalac—355 to 600 μmfraction) by tumbling. The powder was fired from a Cyclohaler at a flowrate of 601/minute in a multi-stage liquid impinger. The fine particlefraction (< approx. 5 μm) was 45%.

EXAMPLE 7

98 g of Microfine (MMAD approximately 8 μm) lactose (manufactured byBorculo) was placed in a stainless steel milling vessel. 300 g ofstainless steel milling balls varying from 10 to 3 mm diameter wereadded. 2 g of lecithin was added and the vessel was located in a RetschS100 Centrifugal Mill. The powder was milled for, 30 minutes at 580 rpmand was then sieved to remove the milling balls.

1 g of salbutamol sulphate was added to 1 g of the composite excipientparticles so obtained containing 2% lecithin, and to 8 g ofsieve-fractionated Prismalac lactose (355 to 600 μm fraction). Themixture was tumbled for 30 minutes at 42 rpm. The resulting powder wasfired from a Cyclohaler at a flow rate of 60 litres per minute into atwin-stage impinger, giving a fine particle fraction (< approx. 5 μm) ofabout 44%. A similar example with a 2% leucine precursor gave a fineparticle fraction (< approx. 5 μm) of 52%.

Other additive materials that may be used instead of lecithin to formcomposite excipient particles as described above are: magnesiumstearate, calcium stearate, sodium stearate, lithium stearate, stearicacid, stearylamine, soya lecithin, sodium stearyl fumarate, l-leucine,1-iso-leucine, oleic acid, starch, diphosphatidyl choline, behenic acid,glyceryl behenate, and sodium benzoate. Pharmaceutically acceptablefatty acids and derivatives, waxes and oils may also be used.

EXAMPLE 8

10 g of Microfine lactose (Borculo) was combined with 1 g of magnesiumstearate and 10 cm³ cyclohexane. 50 g of 5 mm balls were added and themixture was milled for 90 minutes. The powder was recovered by leavingthe paste in a fume hood overnight to evaporate the cyclohexane and thenball milling for 1 minute.

0.5 g of salbutamol sulphate was added to 0.5 g of the compositeexcipient particles so obtained containing magnesium stearate, and to 4g of sieve-fractionated Prismalac lactose (355-600 μm fraction). Thiswas tumbled for 30 minutes at 62 rpm. The resulting powder was firedfrom a Cyclohaler at a flow rate of 60 litres per minute into atwin-stage impinger, giving a fine particle fraction (< approx. 5 μm) of57%. The experiment was repeated using composite excipient particlescontaining 20% magnesium stearate and similar results were obtained.

EXAMPLE 9

10 g of Microfine lactose (Borculo) was combined with 1 g of leucine and10 cm³ cyclohexane. 50 g of 5 mm balls were added and the mixture wasmilled for 90 minutes. The powder was recovered by leaving the paste ina fume hood overnight to evaporate the cyclohexane and then ball millingfor 1 minute.

0.5 g of salbutamol sulphate, 0.25 g of composite excipient particlesmade as described in Example 8 containing magnesium stearate, 0.25 g ofcomposite excipient particles made as described above containingleucine, and 4 g of sieve-fractionated Prismalac (355-600 μm fraction)were all combined. The mixture was tumbled for 30 minutes at 62 rpm. Theresulting powder was fired from a Cyclohaler at a flow rate of 60 litresper minute into a twin-stage impinger, giving a fine particle fraction(< approx. 5 μm) of ˜65%.

EXAMPLE 10

10 g of Microfine lactose (Borculo) was combined with 1 g of lecithinand 10 cm³ cyclohexane. 50 g of 5 mm balls were added and the mixturewas milled for 90 minutes. The powder was recovered by leaving the pastein a fume hood overnight to evaporate the cyclohexane and then ballmilling for 1 minute.

0.5 g of salbutamol sulphate was added to 0.25 g of the compositeexcipient particles so obtained containing lecithin, 0.25 g of compositeexcipient particles made as described in Example 9 containing leucine,and 4 g of sieve-fractionated Prismalac lactose (355-600 μm fraction).The mixture was tumbled for 30 minutes at 62 rpm. The resulting powderwas fired from a Cyclohaler at a flow rate of 60 litres per minute intoa twin-stage impinger, giving a fine particle fraction (< approx. 5 μm)of 68%.

EXAMPLE 11

95 g Sorbolac 400 (Meggle) were combined with 5 g of magnesium stearateand 50 ml dichloromethane and milled in a Retsch 5100 centrifugal millwith 620 g of 5 mm stainless steel balls in a stainless steel vessel for90 minutes at 500 rpm. The powder was recovered after evaporation of thedichloromethane by briefly milling (1 minute) and subsequent sieving. 10g of the composite excipient/additive particles so obtained were addedto 89.5 g of sieve fractionated Prismalac lactose (355-600 μm fraction):The mixture was tumbled for 30 minutes at 60 rpm, then 0.5 g budesonidewas added and tumbling continued for a further 30 minutes at 60 rpm. Thepowder was fired from a Cyclohaler at 601/minute into a Twin-StageImpinger, and gave a fine particle fraction (< approx. 5 μm) of about80%.

EXAMPLE 12

(a) A pre-blend was made by milling an additive material and microfinelactose (<20 micron) together in a ball mill. Then 1 g of the pre-blend,1 g of salbutamol sulphate and 8 g of coarse lactose (Prismalac 355-600μm fraction) were mixed together in a glass vessel in a Turbula mixer at42 rpm to create the final formulation. Size 2 capsules were filled with20 mg of the formulation. For each test, 3 capsules were fired into a‘rapid TSI’ from a cyclohaler giving a total delivered dose of 6 mg ofsalbultamol sulphate per test. The additive material was selected fromlithium stearate, calcium stearate, magnesium stearate, sodium stearate,sodium stearyl fumarate, leucine, lecithin and stearylamine.(b) The method of (a) above was repeated using leucine, except that thepre-blend was mixed with the coarse lactose in a glass vessel shaken byhand.

The “rapid TSI” is a modified methodology based on a conventional TSI.In the rapid TSI the second stage of the impinger is replaced by a glassfibre filter (Gelman A/E, 76 mm). This enables the fine particlefraction of the formulation (i.e. particles with an MMAD<5 um) to becollected on a filter for analysis. Analysis was conducted by sonicatingthe filter in a 0.06M NaOH solution and analysed at 295 nm on a UVspectrophotomer (Spectronic 601). The fine particle fraction correspondssubstantially to the respirable fraction of the formulation.

Further details of the formulations and the % fine particle fractionestimated using the “rapid TSI” method described above are given inTable 4 below.

Segregation has not been observed in the above formulations, even thosecomprising 10 and 20% magnesium stearate (i.e. up to 2% in the finalcomposition).

The above processes have been applied to a variety of active materials.When the active material is a protein, the milling may be preceded bylyophilisation (freeze drying) of the protein either pure or incombination with an additive material and/or a polymeric stabiliser. Thefreeze drying may make the protein more brittle and more easily milled.The milling may need to be conducted under cryogenic (cold) conditionsto increase the brittleness of the material.

TABLE 4 Additive % AM in Estimat- Material % AM in formu- Mass (mg) ed %Pre-blend (“AM”) pre-blend lation SaS04 FPF mill method Lithium St 2 0.22.549 42 30 mins 2.763 46 Calcium St 2 0.2 2.721 45 1 hr 2.633 44Magnesium 2 0.2 2.108 35 1 hr St 2.336 39 Sodium St 2 0.2 3.218 54 30mins 3.153 53 Sodium 2 0.2 2.261 38 30 mins stearyl 2.113 35 FumarateLeucine 2 0.2 2.429 40 2 hrs 2.066 34 Leucine 2 0.2 2.136 36 2 hrs[12(b)] 2.600 43 Leucine 5 0.5 2.782 46 30 mins 3.000 50 Leucine 5 0.52.772 46 5 hrs 2.921 49 Magnesium 5 0.5 2.438 41 30 mins St 2.721 45Lecithin 2 0.2 3.014 50 30 mins 2.884 48 Stearylamine 2 0.2 2.847 47 30mins 3.037 51

EXAMPLE 13

Determination of the suitable amount of magnesium stearate to be addedin the formulation.

Samples of pre-blends were prepared by co-milling in a ball millingapparatus for 2 hours α-lactose monohydrate SorboLac 400 (Megglemicrotose) with a starting particle size below 30μ(d(v, 0.5) of about 10μm) and magnesium stearate with a starting particle size of 3 to 35 μm(d(v, 0.5) of about 10 μm) in the ratio 98:2, 95:5 and 90:10% by weight(blends A).

85% by weight of a-lactose monohydrate CapsuLac (212-355 μm) was placedin a 240 ml stainless steel container, then 15% by weight of arespective blend A was added. The blend was mixed in a Turbula mixer for2 hours at 42 rpm (blend B). Micronised formoterol fumarate was added tothe blend B and mixed in a Turbula mixer for 10 mins at 42 rpm to obtaina ratio of 12 μg of active to 20 mg of carrier. The final formulation(hard pellet formulation) was left to stand for 10 mins then transferredto an amber glass jar.

The amount of magnesium stearate in the final formulations turns out tobe 0.3, 0.75 and 1.5% by weight, respectively. The uniformity ofdistribution of active ingredient and the in-vitro aerosol performancewere determined as follows:

a) The uniformity of distribution of the active ingredient was evaluatedby withdrawing 10 samples, each equivalent to about a single dose, fromdifferent parts of the blend. The amount of active ingredient of eachsample was determined by High-Performance Liquid Chromatography (HPLC).b) Determination of the aerosol performances.An amount of powder for inhalation was loaded in a multidose dry powderinhaler (Pulvinal®—Chiesi Pharmaceutical SpA, Italy).

The evaluation of the aerosol performances was performed by using amodified Twin Stage Impinger apparatus, TSI (Apparatus of type A for theaerodynamic evaluation of fine particles described in FU IX, 4°supplement 1996). The equipment consists of two different glasselements, mutually connected to form two chambers capable of separatingthe powder for inhalation depending on its aerodynamic size; thechambers are referred to as higher (stage 1) and lower (stage 2)separation chambers, respectively. A rubber adaptor secures theconnection with the inhaler containing the powder. The apparatus isconnected to a vacuum pump which produces an air flow through theseparation chambers and the connected inhaler. Upon actuation of thepump, the air flow carries the particles of the powder mixture, causingthem to deposit in the two chambers depending on their aerodynamicdiameter. The apparatus used were modified in the Stage 1 Jet in orderto obtained an aerodynamic diameter limit value, dae, of 5 μm at an airflow of 30 l/min, that is considered the relevant flow rate forPulvinal® device. Particles with higher dae deposit in Stage 1 andparticles with lower dae in Stage 2. In both stages, a minimum volume ofsolvent is used (30 ml in Stage 2 and 7 ml in Stage 1) to preventparticles from adhering to the walls of the apparatus and to promote therecovery thereof.

The determination of the aerosol performances of the mixture obtainedaccording to the preparation process a) was carried out with the TSIapplying an air flow rate of 30 l/min for 8 seconds.

After nebulization of 10 doses, the Twin Stage Impinger was disassembledand the amounts of drug deposited in the two separation chambers wererecovered by washing with a solvent mixture, then diluted to a volume of100 and 50 ml in two volumetric flasks, one for Stage 1 and one forStage 2, respectively. The amounts of active ingredient collected in thetwo volumetric flasks were then determined by High-Performance LiquidChromatography (HPLC). The following parameters, were calculated: i) theshot weight expressed as mean and relative standard deviation (RSD) ii)the fine particle dose (FPD) which is the amount of drug found in stage2 of TSI; iii) the emitted dose which is the amount of drug deliveredfrom the device recovered in stage 1+stage 2; iv) the fine particlefraction (FPF) which is the percentage of the emitted dose reaching thestage 2 of TSI.

TABLE 5 Uniformity of distribution and in-vitro aerosol performances Mgstearate 0.3% Mg stearate 0.75% Mg stearate 1.5% Content uniformity Mean(μg) 11.84 — — RSD (%) 1.83 — — Shot weight Mean (mg) 20.8 24.7 23.04.28 49.9 RSD (%) 6.9 6.5 2.4 Emitted dose 8.57 10.1 11.1 (μg) FPD (μg)4.28 3.5 3.6 FPF (%) 49.9 35 32

In all cases, good performances in terms of fine particle dose areobtained, in particular with 0.3% by weight of magnesium stearate in thefinal formulation.

EXAMPLE 14 Effect of the Addition of Magnesium Stearate by Simple MixingFormulation A

α-Lactose monohydrate Pharmatose 325M (30-100 μm) and magnesium stearatein the ratio 99.75:0.25% by weight were blended in a Turbula mixer for 2hours at 42 rpm. The blend was mixed with formoterol fumarate in aTurbula mixer for 30 mins at 42 rpm to obtain a ratio of 12 μg of activeto 25 mg of carrier.

Formulation B

as reported above but α-Lactose monohydrate SpheroLac 100 (90-150 μm)was used instead of Pharmatose 325M.

Formulation C

α-Lactose monohydrate PrismaLac 40 (with a particle size below 355 μm)and micronised lactose with a particle size below 5 μm in the ratio40:60% by weight were mixed in a Turbula mixer for 60 mins at 42 rpm99.75% by weight of the resulting blend and 0.25% by weight of magnesiumstearate were mixed in a Turbula mixer for 60 mins at 42 rpm. Theresulting blend was finally mixed with formoterol fumarate in a Turbulamixer for 30 mins at 42 rpm to obtain a ratio of 12 μg of active to 15mg of carrier.

Formulation D

Sorbolac 400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm)and magnesium stearate in the ratio 98:2% by weight were mixed in a highshear mixer for 120 mins (blend A). 85% by weight α-lactose monohydrateCapsuLac (212-355 μm) and 15% by weight of blend A were mixed in Turbulafor 2 hours at 42 rpm (blend B); the amount of magnesium stearate in thefinal formulation is 0.3% by weight. Micronised formoterol fumarate wasplaced on the top of blend B and mixed in a Turbula mixer for 10 mins at42 rpm to obtain a ratio of 12 μg of active to 20 mg of carrier.

Formulation F

Micronized lactose with a particle size below 10 μm (d(v, 0.5) of about3 μm) and magnesium stearate in the ratio 98:2% by weight were mixed ina Sigma Blade mixer for 60 mins (blend A). 85% by weight of α-lactosemonohydrate CapsuLac (212-355 μm) and 15% by weight of blend A weremixed in Turbula for 2 hours at 42 rpm (blend B); the amount ofmagnesium stearate in the final formulation is 0.3% by weight.Micronised formoterol fumarate was placed on the top of blend B andmixed in a Turbula mixer for 10 mins at 42 rpm to obtain a ratio of 12μg of active to 20 mg of carrier.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances were determined as described inExample 13 and are reported in Table 6.

TABLE 6 Uniformity of distribution of active ingredient and in-vitroaerosol performances Formula- Formula- Formula- Formula- Formula- tionsA tions B tions C tions D tions E Content uniformity Mean (μg) 7.9610.50 9.10 10.68 11.32 RSD (%) 2.16 8.30 24.90 2.80 3.0 Shot weight Mean(mg) 24.10 26.50 12.50 22.07 21.87 RSD (%) 34.60 8.20 15.30 2.50 4.0Emitted dose 6.10 7.60 9.60 8.60 9.93 (μg) FPD (μg) 0.60 0.90 1.60 3.384.80 FPF (%) 9.8 11.8 16.7 39.3 48.37

Formulations where magnesium stearate is added by a high energy mixingto a small amount of fine lactose (blend A of the formulations D and E),and combined with a 212-355 μm coarse lactose fraction, show asignificant increase in performance. In addition, the particle size ofthe fine lactose used has a significant effect on the deaggregationproperties of the final formulation; in fact, formulation E preparedusing a micronized lactose shows a significant improved performancecompared with formulation D.

EXAMPLE 15 Effect of the Amount of Micronized Pre-Blend in the FinalFormulation

α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with a startingparticle size of 50 to 400 μm (d(v, 0.5) of about 170 μm and magnesiumstearate with a starting particle size of 3 to 35 μm (d(v, 0.5) of about10 μm) in the ratio 98:2% by weight were co-milled in a jet millapparatus (blend A) Different ratios of α-lactose monohydrate Capsulac(212-355 μm) and blend A were placed in a stainless steel container andmixed in a Turbula mixer for four hours at 32 rpm (blends B).

Micronised formoterol fumarate was placed on the top of blends B andmixed in a Turbula mixer for 30 mins at 32 rpm to obtain a ratio of 12μg of active to 20 mg total mixture. The amount of magnesium stearate inthe final formulation ranges between 0.05 and 0.6% by weight.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances were determined as in Example 13 andare reported in Table 7.

TABLE 7 Uniformity of distribution of active ingredient and in-vivoaerosol performance Ratio Ratio Ratio Ratio Ratio Ratio 97.5:2.5 95:592.5:7.5 90:10 80:20 70:30 Content uniformity Mean (g) 11.29 12.25 11.5311.93 11.96 12.00 RSD (%) 3.8 5.7 1.5 2.5 2.0 2.0 Shot weight Mean (mg)19.27 20.26 20.38 21.05 22.39 22.48 RSD (%) 4.7 3.3 3.2 4.3 3.5 3.7Emitted dose (μg) 10.58 9.20 10.65 9.18 9.63 9.88 FPD (μg) 4.18 5.106.78 5.9 5.33 5.28 FPF (%) 39.4 55.4 63.6 64.3 55.3 53.4

The results indicate that the performances of all the formulations aregood.

EXAMPLE 16

10 g of the composite excipient particles containing 5% magnesiumstearate obtained in accordance with Example 11 were mixed with 89:5 gcoarse lactose (Prismalac; 355-600 μm fraction) in a Turbula mixer for30 minutes. 0.5 g micronised dihydroergotamine mesylate was added andmixing continued in the Turbula for a further 30 minutes. The powder wasfired from a Cyclohaler into a Multi-Stage Liquid Impinger (Apparatus C,European Pharmacopoeia, Method 5.2.9.18, Supplement 2000), and gave afine particle fraction (< approx. 5 μm) of about 60%.

EXAMPLE 17

Composite excipient particles were manufactured by milling 95 g finelactose (Sorbolac 400—Meggle) with 5 g magnesium stearate and 50 mldichloromethane in a Retsch S100 centrifugal mill with 620 g of 5 mmstainless steel balls in a stainless steel vessel for 90 minutes at 500rpm. The powder was recovered after evaporation of the dichloromethaneby briefly milling (1 minute) and subsequent sieving, 10 g of thecomposite excipient/additive particles so obtained were added to 89.5 gof sieve fractionated Prismalac lactose (355-600 μm fraction). Themixture was tumbled in a Turbula mixer for 30 minutes at 60 rpm, then0.5 g fentanyl citrate was added and tumbling continued for a further 30minutes at 60 rpm. The powder so obtained was fired from a Cyclohaler at601/min into a Twin-Stage Impinger, and gave a fine particle fraction (<approx. 5 μm) of about 50%.

EXAMPLE 18

Various formulations, each combining 89.5 g, 10 g composite excipientparticles and 0.5 g budesonide were made according to the method ofExample 11.

Their flowabilities were then measured using a FLODEX (trade mark)tester, made by Hanson Research. The FLODEX provides an index, over ascale of 4 to 40 mm, of flowability of powders. Analysis was conductedby placing 50 g of formulation into the holding chamber of the FLODEXvia a funnel, allowing the formulation to stand for 1 minute, and thenreleasing the trap door of the FLODEX to open an orifice at the base ofthe holding chamber. Orifice diameters of 4 to 34 mm were used tomeasure the index of flowability. The flowability of a given formulationis determined as the smallest orifice diameter through which flowing ofthe formulation is smooth.

The results are shown in Table 8.

Comparison data is given for a formulation made by mixing for 30 minutesin a Turbula mixer 45 g Pharmatose 325M lactose (a lactose used incertain conventional formulations) and 5 g microfine lactose.

TABLE 8 Flow- Carrier particles Composite particles ability Prismalac355-600 Leucine:Sorbolac400 1:9 <4 mm Prismalac 355-600Lecithin:Sorbolac400 1:9 <4 mm Prismalac 355-600 Magnesiumstearate:Sorbolac400 1:19 <4 mm Prismalac 355-600 Magnesiumstearate:microfine lactose <4 mm 1:19 Pharmatose 325M Microfine lactose<34 mm 

The results in Table 8 illustrate the excellent flowability of theformulations according to the invention.

COMPARISON EXAMPLE 1

99.5 g of sieve-fractionated Prismalac (355-600 μm fraction) was tumbledwith 0.5 g budesonide for 30 minutes at 60 rpm. The powder, fired from aCyclohaler at 90 litres per minute into a Multi-Stage Liquid Impingergave a fine particle fraction (< approx. 5 μm) of about 30%.

1. A formulation for use in an inhaler device, comprising carrierparticles having a diameter of at least 50 μm and a mass median diameterof at least 175 μm; active patents and additive material which is ableto promote release of the active particles from the carrier particles onactuation of the inhaler device, the formulation comprising more than 5%by weight, based on the total weight of the formulation, of particles ofaerodynamic diameter less than 20 μm, and the formulation having aflowability index of 12 mm or less.
 2. A formulation according to claim1, in which the mass median diameter of the carrier particles is atleast 200 μm.
 3. (canceled)
 4. (canceled)
 5. A formulation according toclaim 1, in which the carrier particles are of lactose.
 6. A formulationaccording to claim 1, in which the carrier particles are of a materialhaving a fissured surface.
 7. A formulation according to claim 1, inwhich the carrier particles are of a crystalline sugar having a tappeddensity not exceeding 0.75 g/cm³.
 8. (canceled)
 9. A formulationaccording to claim 1, in which the carrier particles have a bulk densityas measured by mercury intrusion porosimetry of not exceeding 0.6 g/cm³.10. A formulation according to claim 1, in which the carrier particlesare in the form of an agglomerate consisting of a plurality of crystalsfused to one another.
 11. (canceled)
 12. (canceled)
 13. (canceled)
 14. Aformulation according to claim 1, in which the additive material ispresent in an amount of not more than 10% by weight based on the totalweight of the formulation.
 15. (canceled)
 16. (canceled)
 17. (canceled)18. (canceled)
 19. (canceled)
 20. (canceled)
 21. A formulation accordingto claim 1, in which the additive material comprises one or morecompounds selected from the group consisting of magnesium stearate,calcium stearate, sodium stearate, stearate, stearic acid, stearylamine,sodium stearyl fumarate, oleic acid, starch, behenic acid, glycerylbehenate and sodium benzoate.
 22. A formulation according to claim 21,in which the additive is magnesium stearate.
 23. (canceled)
 24. Aformulation according to claim 1, in which the additive material is inparticulate form.
 25. A formulation according to claim 24, in which atleast 90% by weight of the additive particles have an aerodynamicdiameter of less than 100 μm.
 26. A formulation according to claim 24,in which the mass median aerodynamic diameter of the additive particlesis not more than about 100 μm.
 27. A formulation according to claim 1,which comprises not less than 0.01% by weight of additive material basedon the weight of the formulation.
 28. (canceled)
 29. (canceled) 30.(canceled)
 31. A formulation according to claim 1, which contains up to50% by weight of active particles, based on the total weight of activeparticles, additive material and carrier particles.
 32. (canceled)
 33. Aformulation according to claim 1, which comprises at least 50% by weightcarrier particles, based on the total weight of the formulation. 34.(canceled)
 35. A formulation according to claim 1, in which the activeparticles comprise a therapeutically active agent for the prevention ortreatment of respiratory disease.
 36. (canceled)
 37. A formulationaccording to claim 35, in which active particles comprise atherapeutically active agent having systemic activity.
 38. (canceled)39. (canceled)
 40. A formulation according to claim 1, which furthercomprises fine particles of an excipient material of aerodynamicdiameter not more than 50 μm.
 41. A formulation according to claim 40,in which the mass median aerodynamic diameter of the fine excipientparticles is not more than 15 μm.
 42. (canceled)
 43. A formulationaccording to claim 40, which includes the fine excipient particles in anamount of not less than 4% by weight, based on the total weight of theformulation.
 44. A formulation according to claim 40, including fineexcipient particles in an amount of up to 20% by weight, based on thetotal weight of the formulation.
 45. (canceled)
 46. (canceled) 47.(canceled)
 48. (canceled)
 49. A formulation according to claim 40,comprising up to 20% by weight fine excipient particles and up to 10% byweight additive material, based on the total weight of the formulation.50. A formulation according to claim 1, which comprises up to 10% byweight additive material, based on the total weight of the formulation.51. (canceled)
 52. (canceled)
 53. A formulation for use in an inhalerdevice, comprising: from 5 to 90% by weight carrier particles having adiameter of at least 50 μm and a mass median diameter of at least 175μm; from 0.01 to 90% by weight of a therapeutically active agent; from0.01 to 50% by weight of an additive material which is able to promotereleased of the active material on actuation of the inhaler device; ineach case, by weight, based on the total weight of the carrierparticles, active agent and additive material.
 54. (canceled) 55.(canceled)
 56. (canceled)
 57. (canceled)
 58. (canceled)
 59. (canceled)60. An inhaler device comprising a formulation according to claim
 1. 61.(canceled)
 62. (canceled)
 63. A method of manufacturing a formulationaccording to claim 1, comprising mixing the additive material with thecarrier particles and the active particles.
 64. A method according toclaim 63, in which the additive material is mixed with fine excipientmaterial before mixing with the carrier particles and the activeparticles.
 65. A method of increasing the fine particle fractionobtainable from a formulation for an inhaler device comprising combiningfissured carrier particles of mass median diameter of at least 175 μmwith an additive material.
 66. A formulation according to claim 1,comprising composite particles comprising additive material and fineexcipient material consisting of one or more crystalline sugars,prepared as a pre-blend by milling or high-energy mixing the additiveand fine excipient material prior to the addition of the active andcarrier particles; wherein the additive material includes one or morecompounds selected from amino acids and derivatives thereof; peptidesand polypeptides having a molecular weight from 0.25 to 1000 Kda, andderivatives thereof; phospholipids or a derivative thereof; fatty acidsand derivatives thereof; or a surface active material.
 67. A formulationaccording to claim 1, wherein said carrier particles have no tendency todisintegrate on expulsion from the inhaler device.
 68. A methodaccording to claim 63, comprising forming composite particles comprisingadditive material and fine excipient material consisting of one or morecrystalline sugars, prepared as a pre-blend by milling or high-energymixing the additive and fine excipient material prior to the addition ofthe active and carrier particles; wherein the additive material includesone or more compounds selected from amino acids and derivatives thereof;peptides and polypeptides having a molecular weight from 0.25 to 1000Kda, and derivatives thereof; phospholipids or a derivative thereof;fatty acids and derivatives thereof; or a surface active material.